Nonionic contrast agents for intravascular and central nervous system visualization are complex molecules. As is known, the iodine in the molecule provides opacification to the X-rays, while the remainder of the molecule provides the framework for transport of the iodine atoms. However, the structural arrangement of the molecule is important in providing stability, solubility and biological safety in various organs. A stable carbon-iodine bond is achieved in most compounds by attaching it to an aromatic nucleus. An enhanced degree of solubility as well as safety is conferred on the molecule by the addition of suitable solubilizing and detoxifying groups. Further, nonionic contrast agents are particularly desirable compared to contemporary ionic agents due to the minimization of those pharmacological effects associated with colligative properties, e.g., osmolality.
Several of the features that are desirable for intravascular and central nervous system nonionic contrast agents are often incompatible so that all such agents represent compromises. In searching for the best compromise, the controlling factors are pharmacological inertness, i.e., in vivo safety, and high water solubility. Thus, the ideal intravascular or central nervous system nonionic agent represents a compromise in an attempt to obtain the following criteria: (1) maximum opacification to X-rays; (2) pharmacological inertness; (3) high water solubility; (4) stability; (5) selective excretion; (6) low viscosity; and (7) minimal osmotic effects.
Illustrative nonionic contrast agents include N,N'-bis(2,3-dihydroxypropyl)-5-N-(2-hydroxyethyl)glycolamido-2,4,6-triiod oisophthalamide (Lin, U.S. Pat. No. 4,396,598) and 5-N-(2,3-dihydroxypropyl)acetamido-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypro pyl)isophthalamide (Nordal et al., U.S. Pat. No. 4,250,113 and Rakli et al. U.S. Pat. No. 4,396,597).
There is a continuing need for nonionic contrast agents which meet all or substantially all of the foregoing criteria. It is an object of the present invention to provide nonionic X-ray contrast agents which substantially meet these criteria. It is a further object of this invention to provide nonionic X-ray contrast agents with improved pharmacological inertness, i.e., low toxicity, by means of the incorporation of highly hydrophilic side chains. It is a still further object of this invention to provide chemically stable nonionic X-ray contrast agents having low osmolality. Other objects and features will be in part apparent and in part pointed out hereinafter.